Voltage-gated calcium channels can be divided into high- and low-threshold types. The high-threshold channels include the dihydropyridine-sensitive L-type, the ω-conotoxin GVIA-sensitive N-type and ω-agatoxin IVA-sensitive P-type. Depending on the tissue, these channel subtypes consist of α1, α2δ, β and γ subunits. (Perez-Reyes and Schneider (1995) Kid. Int. 48:1111-1124.) To date, only one type of low-threshold calcium channel is known, the T-type calcium channel.
T-type calcium channels have hyperpolarized steady-state inactivation characteristics, a low threshold for inactivation, small single channel conductance and display rapid inactivation kinetics. (Ertel and Ertel (1997) Trends Pharmacol. Sci. 18:37-42.) The functional roles for T-type calcium channels in neurons include membrane depolarization, calcium entry and burst firing. (White et al. (1989) Proc. Natl. Acad. Sci. USA 86:6802-6806.) T-type calcium channels are found in many neurons of the central and peripheral nervous systems, including small and medium diameter neurons of the dorsal root ganglia (Scroggs and Fox (1992) J. Physiol. 445:639-658) and neurons in the thalamus. (Suzuki and Rogawski (1989) Proc. Natl. Acad. Sci. USA 86:7228-7232.) Calcium currents have been found to be important in several neurological and muscular functions, e.g., pain transmission, cardiac pacemaker activity, etc. Improper functioning of these channels has been implicated in arrythmias, chronic peripheral pain, improper pain transmission in the central nervous system, and epilepsy.
Anti-epileptic drugs are known to cause a reduction of the low-threshold calcium current (LTCC or T-type Ca2+ current) in thalamic neurons. (Coulter et al. (1989) Ann. Neurol. 25:582-593.) One such anti-epileptic compound, ethosuximide, has been shown to fully block T-type Ca2+ current in freshly dissected neurons from dorsal root ganglia (DRG neurons) of adult rats (Todorovic and Lingle (1998) J. Neurophysiol. 79:240-252), and may have limited efficacy in the treatment of abnormal, chronic pain syndromes that follow peripheral nerve damage.
Molecular cloning has revealed the cDNA and corresponding amino acid sequences of several different α1 subunits (α1A, α1B, α1C, α1D, α1E, α1G, α1H, α1I, and α1S). While the cloned α1 subunits identified thus far correspond to several of the calcium channels found in cells, they do not account for all types of calcium conductance found in native cells.
The present invention relates to the discovery of human T-type calcium channel α1I subunit variants that are useful in diagnosis of disease states associated with the peripheral nervous system and for screening compounds that may be used in the treatment of mammals for these disease states.